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Gene mutation affects the course of rheumatoid arthritis
By Lone Frank

According to a new Danish study, patients with rheumatoid arthritis are likely to have more serious disease if they carry genetic mutations that cause low levels of the immune protein MBL (Mannose-binding lectin). The results suggest that detection of MBL mutations followed by treatment with MBL may help a large group of patients.

"Carrying MBL mutations does not in itself increase the risk of developing arthritis, but once the disease is manifest such mutations seem to cause it to progress twice as fast as normal and develop much more severely", says study leader Niels Graudal of the National University Hospital in Copenhagen. Rheumatoid arthritis is an autoimmune disease in which the joints come under attack from immune cells, which causes swelling and inflammation; eventually the painful condition causes destruction and deformation of cartilage and ultimately bone tissue. Jørgen Petersen, a rheumatologist at the Rigshospitalet, Copenhagen University Hospital, says, "This study surprises by showing that the lack of a defensive immune protein can have a negative effect". He is convinced that the discovery of MBL's role in arthritis can lead to better treatment of mutations carriers, "if this patient group is identified by genetic testing early and aggressive medical treatment becomes an option", he says.

The new study provides a starting point for investigating how low levels of MBL affect arthritic processes, and according to co-author Peter Garred, an immunologist at the National University Hospital, "it is possible that the protein modifies aspects of inflammation". Despite a great interest in genetics, researchers have so far identified very few genes involved, and they only increase the disease risk marginally.

"We looked at MBL because it is implicated in other auto-immune diseases", Garred reports. The MBL protein circulates in blood and acts in the body's first line of defence against infections, and while the normal MBL gene is designated A, the term O is used for three known variations. Carrying one O copy causes low MBL production, and patients with two copies produce no detectable protein. The Danish team tested MBL levels and MBL genotype in 140 arthritic patients who enrolled in a long term arthritis study in 1966 and have been followed with yearly examinations ever since. One out of five patients carried at least one O variation matching the frequency among Caucasians in general.

Presently there is no cure for rheumatoid arthritis, and treatment is designed to ease the painful symptoms by reducing joint inflammation. New generations of drugs focus on blocking production of immune proteins that stimulate inflammation. In the longer term, Garred believes in treating with MBL itself. "It is likely that supplementing MBL-insufficient patients with the protein will slow down the disease progression and have a positive effect on the final outcome". With collaborators at Copenhagen's Serum Institute who are currently producing MBL protein, Garred plans to move into clinical testing of MBL.

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Graudal, N.A., et al. The association of variant Mannose-binding lectin genotypes with radiographic outcome in Rheumatoid Arthritis. Arthritis Rheum 43, 515-521 (March 2000).

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